Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome
Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren’s syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that gluta...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
|
| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/3210200 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832559524115906560 |
|---|---|
| author | Jiayao Fu Yiping Pu Baoli Wang Hui Li Xiujuan Yang Lisong Xie Huan Shi Zhijun Wang Junhao Yin Tianle Zhan Yanxiong Shao Changyu Chen Qi Luo Jiabao Xu Zirui Zong Xindi Wei Wanwen Xiao Chuangqi Yu Lingyan Zheng |
| author_facet | Jiayao Fu Yiping Pu Baoli Wang Hui Li Xiujuan Yang Lisong Xie Huan Shi Zhijun Wang Junhao Yin Tianle Zhan Yanxiong Shao Changyu Chen Qi Luo Jiabao Xu Zirui Zong Xindi Wei Wanwen Xiao Chuangqi Yu Lingyan Zheng |
| author_sort | Jiayao Fu |
| collection | DOAJ |
| description | Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren’s syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS. |
| format | Article |
| id | doaj-art-e575da93f1394c72825eade0ed1083e4 |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-e575da93f1394c72825eade0ed1083e42025-02-03T01:29:53ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/3210200Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s SyndromeJiayao Fu0Yiping Pu1Baoli Wang2Hui Li3Xiujuan Yang4Lisong Xie5Huan Shi6Zhijun Wang7Junhao Yin8Tianle Zhan9Yanxiong Shao10Changyu Chen11Qi Luo12Jiabao Xu13Zirui Zong14Xindi Wei15Wanwen Xiao16Chuangqi Yu17Lingyan Zheng18Department of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryDepartment of Oral SurgeryCollege of StomatologyCollege of StomatologyCollege of StomatologyDepartment of Oral SurgeryDepartment of Oral SurgeryPrevious studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren’s syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.http://dx.doi.org/10.1155/2022/3210200 |
| spellingShingle | Jiayao Fu Yiping Pu Baoli Wang Hui Li Xiujuan Yang Lisong Xie Huan Shi Zhijun Wang Junhao Yin Tianle Zhan Yanxiong Shao Changyu Chen Qi Luo Jiabao Xu Zirui Zong Xindi Wei Wanwen Xiao Chuangqi Yu Lingyan Zheng Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome Journal of Immunology Research |
| title | Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome |
| title_full | Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome |
| title_fullStr | Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome |
| title_full_unstemmed | Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome |
| title_short | Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren’s Syndrome |
| title_sort | pharmacological inhibition of glutaminase 1 normalized the metabolic state and cd4 t cell response in sjogren s syndrome |
| url | http://dx.doi.org/10.1155/2022/3210200 |
| work_keys_str_mv | AT jiayaofu pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT yipingpu pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT baoliwang pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT huili pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT xiujuanyang pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT lisongxie pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT huanshi pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT zhijunwang pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT junhaoyin pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT tianlezhan pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT yanxiongshao pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT changyuchen pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT qiluo pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT jiabaoxu pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT ziruizong pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT xindiwei pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT wanwenxiao pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT chuangqiyu pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome AT lingyanzheng pharmacologicalinhibitionofglutaminase1normalizedthemetabolicstateandcd4tcellresponseinsjogrenssyndrome |